ABSTRACT Ovarian cancer (OvCA) ranks fifth in cancer deaths among women, accounting for more deaths than any other gynecologic cancer. Each year, ~22,240 women in the United States will be diagnosed with OvCA, and ~14,070 will die. Ovarian epithelial cancer represents ~90% of all ovarian malignant tumors. The typical pattern of spread and probably the earliest kind of metastasis of OvCA is intraperitoneal spread, ovarian peritoneal carcinomatosis (OPC). OPC is a frequent terminal evolution of OvCA and is considered a lethal condition. In this grant application, we hypothesize that a multimodal approach (a combination of the biochemical agent Fc-TRAIL (immunoglobulin Fc domain fused tumor necrosis factor-related apoptosis-inducing ligand), the chemotherapeutic agent mitomycin C, and mild hyperthermia) will effectively prevent recurrence of OPC by promoting apoptotic death. The specific aims of this project are to: (1) investigate the mechanism of synergistic induction of cytotoxicity by the combinatorial treatment of Fc-TRAIL, mitomycin C, and hyperthermia in OPC organoids; and (2) establish a humanized PDX (patient-derived xenograft) mouse model of OPC and examine the preclinical tumoricidal efficacy of the multimodal approach. In the first aim, we will employ biochemical and molecular techniques to investigate the mechanism of apoptotic death during the combinatorial treatment in OPC organoids. In the second aim, we will establish PDX tumor models with humanized triple transgenic NSGTM-SGM3 mice (nonobese diabetic/severe combined immunodeficiency NOD/SCID gamma mice expressing human interleukin-3, granulocyte-macrophage colony-stimulating factor, and stem cell factor) and assess the response to the combinatorial treatment. We believe that since NSG?- SGM3 mice are a proven host for engraftment of human tumors as well as the establishment of human immunity following hematopoietic stem cell transplantation, we expect that humanized PDX mouse models will retain most of the characteristics of the original tumors and reconstituted human immune system. We believe that the successful outcome of this study will support the useful application of the humanized PDX mouse model to assess this novel chimeric TRAIL-based therapy in combination with HIPEC therapy to patients with OPC.